HIV-1 has proved to be an extremely difficult target for vaccine development. Immune correlates of protective immunity against HIV-1 infection remain uncertain. The virus persistently replicates in the infected individual, leading inexorably to disease despite the generation of vigorous humoral and cellular immune responses. HIV-1 rapidly mutates during infection, resulting in the generation of viruses that can escape immune recognition. Unlike other highly diverse viruses (e.g., influenza), there does not appear to be a succession of variants where one prototypical strain is replaced by successive uniform strains. Rather, an evolutionary tree of viral sequences sampled from a large number of HIV-infected individuals form a star-burst pattern with most of the variants roughly equidistant from the center of the tree. HIV-1 viruses can also persist indefinitely as latent proviral DNA, capable of replicating in individuals at a later time.
Currently, several HIV-1 vaccine approaches are being developed, each with its own relative strengths and weaknesses. These approaches include the development of live attenuated vaccines, inactivated viruses with adjuvant peptides and subunit vaccines, live vector-based vaccines, and DNA vaccines. Envelope glycoproteins were considered as the prime antigen in the vaccine regimen due to their surface-exposure, until it became evident that they are not ideal immunogens. This is an expected consequence of the immunological selective forces that drive the evolution of these viruses: it appears that the same features of envelope glycoproteins that dictate poor immunogenicity in natural infections have hampered vaccine development. However, modification of the vaccine recipe may overcome these problems. For example, a recent report of successful neutralization (in mice) of primary isolates from infected individuals with a fusion-competent immunogen supports this idea.
Another approach could be to use natural isolates of HIV-1 in a vaccine recipe. Identification of early variants even from stored specimens near the start of the AIDS epidemic is very unlikely, however. Natural isolates are also unlikely to embody features (e.g., epitopes) that are ideal for a vaccine candidate. Furthermore, any given natural virus isolate will have features that reflect adaptations due to specific interactions within that particular human host. These individual-specific features are not expected to be found in all or most strains of the virus, and thus vaccines based on individual isolates are unlikely to be effective against a broad range of circulating virus.
Another approach could be to include as many diverse HIV-1 isolates as possible in the vaccine recipe in an effort to elicit broad protection against HIV-1 challenge. First, one or more strains are chosen from among the many circulating strains of HIV. The advantage of this approach is that such a strain is known to be an infectious form of a viable virus. However, such a strain will be genetically quite dissimilar to other strains in circulation, and thus can fail to elicit broad protection. A related approach is to build a consensus sequence based on circulating strains, or on strains in the database. The consensus sequence is likely to be less distant in a genetic sense from circulating strains, but is not an estimate of any real virus, however, and thus may not provide broad protection.
Accordingly, there is a need in the art for new effective methods of identifying candidate sequences for vaccine development to prevent and treat HIV infection. The present invention fulfills this and other needs.